The present invention claims priority to application U.S. Provisional Patent Application Serial No. 60/394,174 filed on Jul. 3, 2002. The entire text of the above-referenced disclosure is specifically incorporated herein by reference without disclaimer.
A. Field of the Invention
The invention pertains to the fields of oncology, protein structure and function, and molecular biology. More particularly, the invention relates to the identification of ErbB-2 binding peptides and their use in cancer diagnosis and therapy.
B. Related Art
The erbB-2 proto-oncogene, also known as HER-2 or neu, is frequently altered in human cancers (Hynes and Stem, 1994). ErbB-2, along with three other known homologous proteins, ErbB-1 (epidermal growth factor receptor, EGFR), ErbB-3, and ErbB-4, form the ErbB family or subclass I of receptor tyrosine kinases (RTK)(McInnes and Sykes, 1997). The activation of ErbB receptors leads to stimulation of cell growth and division. Signal transduction in this class of receptor proteins is initiated through the binding of a growth factor to the extracellular domain of the receptor, followed by receptor homo- or heterodimerization, activation of intracellular kinase domain, and tyrosine autophosphorylation (McInnes and Sykes, 1997).
The ligands for the ErbB growth factor receptor tyrosine kinase family are numerous yet similar. All of them are structurally homologous and contain an epidermal growth factor (EGF)-like motif with six cysteines at highly conserved positions defining three disulfide loops that give rise to the tricyclic nature of these proteins. Despite their receptor specificity, most of the ErbB ligands are capable of binding several different receptors. EGF, transforming growth factor α, and betacellulin bind ErbB1 and the ErbB2/ErbB3 heterodimer (Alimandi et al., 1997); neuregulins associate with ErbB-3 and ErbB-4 (Jones et al., 1998); and epiregulin was shown to complex all three receptors, i.e. ErbB-1, ErbB-3, and ErbB-4 (Shelly et al., 1998). No ligand has been found that binds directly to ErbB-2.
Gene amplification and overexpression of ErbB-2 is associated with increased rates of tumor growth and enhanced rates of metastases (Hynes and Stem, 1994). Although ErbB-2 is also expressed at low levels in several normal organs and tissues (De Potter et al., 1989), the elevated levels of ErbB-2 in many human malignancies and its extracellular accessibility makes it an attractive target for the development of tumor-specific agents. The ErbB-2 receptor has been targeted by a variety of substances and modalities, including monoclonal antibodies (Weiner et al., 1995), immunoconjugates (Jinno et al. 1996), vaccines (Disis et al., 1999), anti-sense therapy (Wiechen et al., 1995) and gene therapy (Harris et al., 1994). Recently Herceptin™, a humanized monoclonal antibody against ErbB-2 (Baselga et al., 1998), was approved for the treatment of metastatic breast cancer. Herceptin™ was shown to possess the anti-tumor activity, but it was also found to aggravate doxorubicin-induced cardiac dysfunction and, possibly, be cardiotoxic on its own (Piccart, 1999). Thus, there remains a need to identify improved ErbB-2-specific reagents for the treatment of ErbB-2 related cancers.